Treatment of drug overdose in humans, whether due to therapeutic miscalculation, illicit drug use, or suicide attempt, presents a major problem to the health care industry worldwide. In the United States alone, over 300,000 patients are admitted to the emergency rooms because of drug overdose. Treatment of these patients costs the healthcare industry over ten billion dollars because of hospital expenses and lost employee productivity. This does not include the $80 billion associated with alcohol abuse (Moudgil, B. M., Seventh Year Annual Report. 2001: Engineering Research Center for Particle Science and Technology, University of Florida).
Current treatment protocols for overdosed patients vary with the drug of concern, but are focused on three objectives: prevention of drug absorption, enhancement of drug excretion, and administration of pharmacological antidotes. The first two are accomplished with techniques nonspecific to the ingested drug, such as emesis, gastric lavage, or use of activated charcoal for the former objective, and dialysis or hemoperfusion for the latter. However, since absorption of toxic drugs is very time sensitive, and since these techniques are applied only once a patient reaches the emergency room, they are not as effective as would be desired, with some techniques reported to recover only 30% of the ingested drug (Rumack, B. H., Poisoning: Prevention of absorption, in Poisoning and Overdose, M. J. Bayer and B. H. Rumack, Eds., 1983, p. 13–18). There also currently exist very few specific pharmacological antidotes to the drugs frequently associated with life threatening overdose cases (Moudgil, B. M., Seventh Year Annual Report. 2001: Engineering Research Center for Particle Science and Technology, University of Florida).
An important factor influencing drug distribution in the body is the ability of toxins to bind to blood proteins and tissues. Certain tissues have strong binding affinities for specific toxins, causing localized concentration in that tissue. This is true especially of the kidney and liver, because of their metabolic and excretory functions. Some toxins bind noncovalently to albumin, a blood plasma protein, or other proteins. While bound to protein, the complex becomes pharmacologically inert and is trapped in the bloodstream due to its large size. Only unbound drugs are able to cross lipoprotein membranes and exert an effect. A drug's free molecule concentration is likely to increase during an overdose, since protein-binding sites are more readily saturated. Therefore, it is expected that a patient with low levels of albumin will experience higher toxicity effects than a patient with normal levels (Lu, F., Basic Toxicology: Fundamentals, Target Organs, and Risk Assessment. 3rd ed. 1996, Taylor and Francis: Washington; Fenton, J. J., Toxicology: A Case-Oriented Approach. 2002, CRC Press: Boca Raton; Stine, K. E. and T. M. Brown, Principles of Toxicology. 1996, CRC Press: Boca Raton).
Micron-scale and nano-scale core-shell particulate systems, either hollow or fluid-filled, have become of recent interest. Core-shell particles find important applications in encapsulation of a variety of materials for catalysis and controlled release applications (e.g. drugs, enzymes, pesticides, dyes, etc.); for use as filler in lightweight composites, pigment, or coating materials; and in biomedical implant materials (Putlitz, B. Z. et al., Adv. Mater., 2001, 13:500-+; Walsh, D. and Mann, S., Nature, 1995, 377:320–323; Walsh, D. et al., Adv. Mater., 1999, 11:324–328; Zhong, Z. et al., Adv. Mater., 2002, 12:206–209; Caruso, F., Chem.-Eur. J., 2000, 6:413–419).
Recently, the use of particulate systems as a treatment for patients overdosed on lipophilic drugs has been proposed (Moudgil, B. M., Seventh Year Annual Report. 2001: Engineering Research Center for Particle Science and Technology, University of Florida). Several particulate systems, including microemulsions, polymer microgels, silica nanotubes and nanosponges, and silica core-shell particles, are currently being investigated for this detoxification purpose. It has been proposed that, when intravenously administered to an overdosed patient, such particles will effectively detoxify the patient's circulatory system of the particular lipophilic toxin by either: (a) absorption, from the selective partitioning of the drug molecules from the blood to the hydrophobic core of the particle; or (b) adsorption of the drug molecules onto surfaces of surface-functionalized particles. Furthermore, in order to catalyze the toxin metabolism, and hence its removal from the blood, the immobilization of toxin-specific catabolic enzymes on or within particles is being pursued (Moudgil, B. M., Seventh Year Annual Report. 2001: Engineering Research Center for Particle Science and Technology, University of Florida).
Fabrication of hollow sphere particles has been accomplished using various methods and materials. In general, three fabrication classes are currently employed: sacrificial cores, nozzle reactor systems, and emulsion or phase separation techniques (Caruso, F., Chem.-Eur. J., 2000, 6:413–419; Wilcox, D. L. and Berg, M., in Materials Research Society, 1994, Boston: Materials Research Society). The first involves the coating of a core substrate with a material of interest, followed by the removal of the core by thermal or chemical means. In this manner, hollow particles of yttrium compounds (Kawahashi, N. and Matijevic, E., J Colloid Interface Sci., 1991, 143:103–110), TiO2 and SnO2 (Zhong, Z. et al., Adv. Mater., 2002, 12:206–209), and silica (Caruso, F., Chem.-Eur. J., 2000, 6:413–419) have been synthesized. Nozzle reactor systems make use of spray drying and pyrolysis, and their use has successfully led to the fabrication of hollow glass (Nogami, M. et al., J. Mater. Sci., 1982, 17:2845–2849), silica (Bruinsma, P. J. et al., Chem. Mater., 1997, 9:2507–2512), and TiO2 (Iida, M. et al., Chem. Mater., 1998, 10:3780) particles. Emulsion-mediated procedures, or hollow particle synthesis, is a third common method. This has been used to form latex (Putlitz, B. Z. et al., Adv. Mater., 2001, 13:500-+), polymeric (Pekarek, K. J. et al., Nature, 1994, 367:258–260), and silica core-shell particles (Underhill, R. S. et al., Abstracts of Papers of the American Chemical Society, 2001, 221:545).
Calcium carbonate coated core-shell particles have also been synthesized. By coating polystyrene beads with calcium carbonate, followed by removal of the polymer core, hollow particles in the 1 μm to 5 μm size range have been generated (Walsh, D. and Mann, S., Nature, 1995, 377:320–323; U.S. Pat. No. 5,756,210). Core-shell particles have also been synthesized using water-in-oil (Walsh, D. et al, Adv. Mater., 1999, 11:324–328; Enomae, T., Proceedings of the 5th Asian Textile Conference, 1999, 1:464–467), and water-in-oil-in-water (Hirai, T. et al, Langmuir, 1997, 13:6650–6653; Hirai, T. and Komasawa, I., Kagaku Kogaku Ronbunshu, 2001, 27:303–313) emulsions as templates for calcium carbonate nucleation. In other processes, Lee et al. (Lee, I. et al., Adv. Mater., 2001, 13:1617–1620) and Qi et al. (Qi, L. M. et al., Adv. Mater., 2002, 14:300) respectively use monolayer-protected gold particles and double-hydrophilic block copolymer (DHBC)-surfactant complex micelles as templates for calcium carbonate deposition, resulting in core-shell particles up to 5 μm in diameter.
Some of the calcium carbonate core-shell systems discussed in the scientific literature are generated by using a biomimetic process (Walsh, D. and Mann, S., Nature, 1995, 377:320–323; Walsh, D. et al., Adv. Mater., 1999, 11:324–328; Hirai, T. et al., Langmuir, 1997, 13:6650–6653; Hirai, T. and Komasawa, I., Kagaku Kogaku Ronbunshu, 2001, 27:303–313; Qi, L. M. et al., Adv. Mater., 2002, 14:300). Mineralization in biological systems has been the focus of intense research because their successful mimicry has important implications for the synthetic design of superior materials. Exquisite control of mineral deposition in biosystems is thought to occur partly due to the presence of an insoluble organic matrix, along with modulation of the crystal growth process via soluble macromolecular species, such as acidic proteins and polysaccharides (Lowenstam, H. A. and Weiner, S., On Biomineralization, Oxford University Press: New York, 1989).
As can be understood from the above, there remains a need for a particulate system that is capable of neutralizing or eliminating toxic levels of drugs within a patient in a short period of time, and which can be produced with the high degree of control associated with biomimetic processes.